A (dis)integrated stress response: Genetic diseases of eIF2α regulators

The integrated stress response (ISR) is a conserved mechanism by which eukaryotic cells remodel gene expression to adapt to intrinsic and extrinsic stressors rapidly and reversibly. The ISR is initiated when stress-activated protein kinases phosphorylate the major translation initiation factor eukaryotic translation initiation factor 2alpha (eIF2alpha), which globally suppresses translation initiation activity and permits the selective translation of stress-induced genes including important transcription factors such as activating transcription factor 4 (ATF4). Translationally repressed messenger RNAs (mRNAs) and noncoding RNAs assemble into cytoplasmic RNA-protein granules and polyadenylated RNAs are concomitantly stabilized. Thus, regulated changes in mRNA translation, stability, and localization to RNA-protein granules contribute to the reprogramming of gene expression that defines the ISR. We discuss fundamental mechanisms of RNA regulation during the ISR and provide an overview of a growing class of genetic disorders associated with mutant alleles of key translation factors in the ISR pathway. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease Translation > Translation Regulation RNA in Disease and Development > RNA in Development

Automated summary

The integrated stress response allows eukaryotic cells to rapidly adapt to stress by globally suppressing translation initiation activity and selectively translating stress-induced genes, such as activating transcription factor 4 (ATF4). This mechanism involves the assembly of translationally repressed mRNAs and noncoding RNAs into cytoplasmic RNA-protein granules, and stabilizing polyadenylated RNAs. The reprogramming of gene expression during ISR is governed by regulated changes in mRNA translation, stability, and localization, with mutant alleles of key translation factors in the ISR pathway implicated in genetic disorders.